Portal hypertension (PHT) is a major clinical problem that leads to the death of over 100,000 Americans annually and disproportionately targets minorities and women because of their greater susceptibility to liver disease. Due to our lack of understanding of the etiology of the altered vasoregulation in PHT, treatment has not been directed at reversing these abnormalities. This proposal will determine the role of the proinflammatory cytokine tumor necrosis factor-a (TNF-a) in the development and maintenance of PHT and will further determine whether TNF-a mediates its effect by stimulating the synthesis of the vasodilators nitric oxide (NO) and/or prostacyclin (PGI2). In vivo models of PHT (portal vein ligation, PVL) in wildtype and TNF-a, iNOS, eNOS, COX-l, COXII knockout mice, in conjunction with in vitro co-cultures of endothelial and smooth muscle cells subjected to shear stress and pulse pressure will be used to assess our hypothesis that TNF-a contributes to the hyperemia of PHT by stimulating the activity of eNOS and COX-1, resulting in increased synthesis of NO and PGI2. These experiments should provide valuable information central to our understanding of PHT and lead directly to effective treatment programs.